POS1238 FIRST EVIDENCE FOR EFFICACY OF CAR-T CELL TREATMENT IN REFRACTORY ANTISYNTHETASE SYNDROME
Authors: J. Taubmann, F. Müller, S. Boeltz, J. Knitza, S. Völkl, M. Aigner, A. Kleyer, I. Minnopoulou, F. Locatelli, M. A. D’agostino, R. Gary, S. Krestchmann, S. Kharboutli, D. Mougiakakos, G. Krönke, M. Andreas, G. Schett
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> We previously reported that deep B cell depletion using a single infusion with autologous CD19 chimeric antigen receptor (CAR) T cells induced drug-free clinical remission in patients with severe systemic lupus erythematosus [1,2]. Whether other forms of severe autoimmune disease are sensitive to treatment with CD19 CAR-T cells has been unknown to date. Antisynthetase syndrome (ASS) is a autoimmune disease that affects muscles, joints, skin and lung. ASS can be very severe and life-threatening needing effective and fast treatment. This abstract presents the first evidence that severe ASS is highly sensitive to treatment autologous CD19 CAR-T cells. <h3>Objectives</h3> To test whether administration of CD19 CAR-T cells is tolerable and effective in patients with severe refractory Antisynthetase syndrome. <h3>Methods</h3> Autologous CD19 CAR-T cells were prepared from leukapheresis specimen after enrichment of T cells and transfection with MB-CART19.1 lentiviral vector (Miltenyi) encoding for a 4-1BB based CAR targeting CD19. Cells were expanded for 12 days and 1 million CAR-T cells/kg body weight were administered as a single intravenous infusion after standard conditioning therapy with cyclophosphamide/fludarabine, as described previously [1,2]. All disease related treatments were stopped before CAR-T cell administration. Patients were followed up in inpatient care for the first 10 days after CAR-T cell administration, thereafter weekly until the end of the first month, then monthly for three months and every three months later. Tolerability was assessed by monitoring for Cytokine-Release Syndrome (CRS) and Immune-related effector Cell Neurotoxicity Syndrome (ICANS). Efficacy was assessed by CK levels, good response according 2016 ACR/EULAR total improvement score (TIS), imaging of muscles and lungs and successful cessation of all immunosuppressive treatments including glucocorticoids. <h3>Results</h3> Two anti-Jo1 ASS patients (patient 1: 41year old male, patients 2: 43year old female) were treated with CD19 CAR-T cells. Both patients presented with active myositis with CK levels of 9305 U/l (normal value &lt;190U/l), and 3055U/l, respectively. Patient 1 showed involvement of the muscles, skin and lungs, patient 2 showed involvement of muscles, skin, joints and lungs. Patient 1 did not respond to 5 different immunosuppressive treatments including cyclophosphamide and rituximab, patient 2 did not respond to 10 treatments including cyclophosphamide, rituximab and ocrelizumab. CAR-T cell treatment was well-tolerated. Only mild CRS (grade I) was observed in both patients. Patient 2 had signs of mild self-limited ICANS (grade I discrete ataxia for a few days) two weeks after CAR-T treatment. In patient 1, CAR-T cells expanded to a maximum of 60cells/µl on day 8, in patient 2 to 1524cells/µl on day 8. Expansion of CAR-T cells paralleled with the complete depletion of circulating B cells. B cell aplasia lasted for 119 days in patient 1, while patient 2 is still in B cell aplasia (day 60). Both patients experienced normalization or significant reduction in CK levels (patient 1: CK+120 days: 70 U/l, patient 2: CK+60 days: 311 U/l), major clinical improvement according to the 2016 TIS and could stop all immunosuppressive therapy. Follow-up CT scans of the lung and MRI of the thigh muscles done in patient 1 showed resolution of alveolar inflammation as well as abrogation of inflammatory changes in the thigh muscles and the hamstrings. At the latest follow up (120days and 60days) both patients were in drug-free remission. Also, the highly positive anti-Jo1 antibodies (331 U/l) disappeared after CAR-T cell treatment (5 U/l; cut-off 25U/l, Orgentec ELISA, Mainz, Germany) in patient 1, while patient 2 awaits follow up measurement. <h3>Conclusion</h3> Taken together, these data suggest that CD19 CAR T-cell therapy provides a possibility to intercept with severe ASS leading to drug-free remission, resolution of muscle and lung inflammation and abrogation of disease-associated autoimmunity. <h3>References</h3> [1]Mougiakakos D. et al, N Engl J Med 2021 [2]Mackensen A. et al. Nat Med 2022 <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.